Wynzora (Page 2 of 4)

8.2 Lactation

Risk Summary

There is no information regarding the presence of topically administered calcipotriene and betamethasone dipropionate in human milk, the effects on the breastfed infant, or the effects on milk production. Concentrations of calcipotriene in plasma are low after topical administration, and therefore, concentrations in human milk are likely to be low [see Clinical Pharmacology (12.3)].

It is not known whether topically administered calcipotriene or corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for WYNZORA Cream and any potential adverse effects on the breastfed child from WYNZORA Cream or from the underlying maternal condition.

Clinical Considerations

To minimize potential exposure to the breastfed infant via breast milk, use WYNZORA Cream on the smallest area of skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply WYNZORA Cream directly to the nipple and areola to avoid direct infant exposure.

8.4 Pediatric Use

Safety and effectiveness of the use of WYNZORA Cream in adolescents and pediatric patients under the age of 18 years have not been established.

Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of systemic toxicity when treated with topical corticosteroids. Pediatric patients are, therefore, also at greater risk of HPA axis suppression and adrenal insufficiency with the use of topical corticosteroids including WYNZORA Cream [see Clinical Pharmacology (12.2)].

Systemic toxicities such as Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients, especially those with prolonged exposure to large doses of high potency topical corticosteroids. Local adverse reactions including striae have also been reported with use of topical corticosteroids in pediatric patients.

8.5 Geriatric Use

The trial included 66 subjects ≥ 65 years of age treated with WYNZORA Cream.

No overall differences in safety or effectiveness of WYNZORA Cream were observed between these subjects and younger subjects. All other reported clinical experience has not identified any differences in response between elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out.

11 DESCRIPTION

WYNZORA (calcipotriene and betamethasone dipropionate) Cream contains anhydrous calcipotriene and betamethasone dipropionate intended for topical use.

Calcipotriene is a synthetic vitamin D3 analog.

Chemically, calcipotriene is (5Z,7E,22E,24S)-24-Cyclopropyl-9,10-secochola-5,7,10(19),22 tetraene-1α,3β,24-triol, with the empirical formula C27 H40 O3 , a molecular weight of 412.6, and the following structural formula:

Chemical Structure

Calcipotriene is a white or almost white powder. It is insoluble in water, freely soluble in ethanol and slightly soluble in methylene chloride.

Betamethasone dipropionate is a synthetic corticosteroid.

Betamethasone dipropionate has the chemical name Pregna-1,4-diene-3,20-dione,9-fluoro-11-hydroxy-16-methyl-17,21-bis(1-oxypropoxy)-,(11β,16β), with the empirical formula C28 H37 FO7 , a molecular weight of 504.6, and the following structural formula:

Chemical Structure

Betamethasone dipropionate is a white to almost white crystalline powder. It is practically insoluble in water, freely soluble in acetone and in methylene chloride, sparingly soluble in alcohol.

Each gram of WYNZORA Cream contains 50 mcg of calcipotriene and 0.644 mg of betamethasone dipropionate (equivalent to 0.5 mg of betamethasone). WYNZORA Cream also contains the following inactive ingredients: isopropyl myristate, mineral oil, medium-chain triglycerides, isopropyl alcohol, polyoxyl lauryl ether, poloxamer (407), polyoxyl 40 hydrogenated castor oil, carbomer interpolymer (type A), butylated hydroxyanisole, trolamine, dibasic sodium phosphate, heptahydrate, monobasic sodium phosphate, monohydrate, alpha-tocopherol and purified water.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

WYNZORA Cream combines the pharmacological effects of calcipotriene as a synthetic vitamin D3 analog and betamethasone dipropionate as a synthetic corticosteroid. However, while their pharmacologic and clinical effects are known, the exact mechanisms of their actions in plaque psoriasis are unknown.

12.2 Pharmacodynamics

Vasoconstriction:

In a vasoconstrictor trial in healthy subjects, the skin blanching response of WYNZORA Cream was consistent with a mid-strength corticosteroid when compared with other topical corticosteroids. However, similar blanching scores do not necessarily imply therapeutic equivalence.

Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression:

HPA axis suppression was evaluated in adult subjects with extensive psoriasis involving 20-30% of the body surface area (including scalp). Treatment consisted of once daily application of WYNZORA Cream to the body (including scalp involvement in 75% of the subjects) for up to 8 weeks. Adrenal suppression indicated by 30-minute post-stimulation serum cortisol level of ≤18 mcg/dL was seen in 6 out of 26 subjects (23%) after 4 weeks of treatment, and in 3 out of 25 subjects (12%; one subject with continued suppression from Week 4 and two additional subjects) after 8 weeks of treatment.

There was no trend towards decreasing cortisol levels post-ACTH stimulation with increasing systemic concentration of betamethasone 17-propionate (B17P) measured as AUC0-7 or Cmax or increasing average weekly amount of WYNZORA Cream used.

Effects on Calcium Metabolism:

The effects on calcium metabolism of once daily application of WYNZORA Cream to the body (including scalp involvement in 75% of subjects) for up to 8 weeks were also examined and no cases of hypercalcemia and no clinically relevant changes in urine calcium were reported.

12.3 Pharmacokinetics

Absorption

The pharmacokinetics of WYNZORA Cream was investigated in adult subjects in the same study as described above [see Clinical Pharmacology (12.2)]. Their mean ± SD total body surface area involvement was 25 ± 5 % and 74% of the subjects presented with scalp involvement and with a mean ± SD scalp involvement of 52 ± 40 %. The mean ± SD weekly dose during the 8 weeks of treatment was 79 ± 30 g.

Plasma concentrations of calcipotriene and betamethasone dipropionate and their major metabolites were measured after 4 weeks and 8 weeks of once daily application of WYNZORA Cream.

In most samples, concentrations of the four analytes were below or close to lower limit of quantification (LOQ). One of 27 (4%) subjects had quantifiable levels of calcipotriene at Week 4 and the Cmax and AUC0-7 were 30 pg/mL and 229 pg*h/mL, respectively. For the major metabolite of calcipotriene, MC1080, 3 of 27 (11%) subjects had quantifiable levels at Week 4. The mean ± SD Cmax and AUC0-7 were 30 ± 4 pg/mL and 224 ± 16 pg*h/mL, respectively. No subjects had quantifiable levels of calcipotriene or MC1080 at Week 8.

There were 3 of 27 subjects (11%) with quantifiable levels of betamethasone dipropionate at Week 4. The mean ± SD of Cmax and AUC0-7 were 22 ± 9 pg/mL and 160 ± 36 pg*h/mL, respectively. The major metabolite of betamethasone dipropionate, B17P, was quantifiable in 13 of 27 subjects (48%) at Week 4. The mean ± SD Cmax and AUC0-7 were 96 ± 234 pg/mL and 419 ± 646 pg*h/mL, respectively. No subjects had quantifiable levels of betamethasone dipropionate at Week 8, whereas 7 of 19 (37%) subjects had quantifiable levels of B17P. The mean ± SD Cmax and AUC0-7 were 31 ± 29 pg/mL and 205 ± 142 pg*h/mL, respectively.

Metabolism

Calcipotriene:

Calcipotriene metabolism following systemic uptake is rapid and occurs in the liver. The primary metabolites of calcipotriene are less potent than the parent compound.

Calcipotriene is metabolized to MC1046 (the α,ß-unsaturated ketone analog of calcipotriene), which is metabolized further to MC1080 (a saturated ketone analog). MC1080 is the major metabolite in plasma. MC1080 is slowly metabolized to calcitroic acid.

Betamethasone dipropionate:

Betamethasone dipropionate is metabolized by hydrolysis to betamethasone 17-propionate and betamethasone, including the 6ß-hydroxy derivatives of those compounds. Betamethasone17-propionate (B17P) is the primary metabolite.

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